Brain natriuretic peptide is not reno-protective during renal ischemia-reperfusion injury in the rat.

BACKGROUND: Acute kidney injury (AKI) occurs in 30% of patients undergoing complex cardiovascular surgery, and renal ischemia-reperfusion (I/R) injury is often a contributing factor. A recent meta-analysis observed that perioperative natriuretic peptide administration was associated with a reduction in AKI requiring dialysis in cardiovascular surgery patients. This study was designed to further clarify the potential reno-protective effect of brain natriuretic peptide (BNP) using an established rat model of renal I/R injury. METHODS: The study comprised three groups (n = 10 kidneys each): (1) control (no injury); (2) I/R injury (45 min of bilateral renal ischemia followed by 3 h of reperfusion); and (3) BNP (I/R injury plus rat-BNP pretreatment at 0.01 µg/kg/min). Glomerular filtration rate (GFR) and a biomarker of AKI, urinary neutrophil gelatinase-associated lipocalin (uNGAL), were measured at baseline and at 30 minute intervals post-ischemia. Groups were compared using two-way repeated measures analysis of variance (mean ± SD, significance P < 0.05). RESULTS: Baseline GFR measurements for control, I/R, and BNP groups were 1.07 ± 0.55, 0.88 ± 0.51, and 1.03 ± 0.59 mL/min (P = 0.90), respectively. Post-ischemia, GFR was significantly lower in I/R and BNP compared with controls at 30 min, 1.29 ± 0.97, 0.08 ± 0.04, and 0.06 ± 0.05 mL/min (P < 0.01), and remained lower through 3 h, 1.79 ± 0.44, 0.30 ± 0.17, and 0.32 ± 0.12 mL/min (P < 0.01). Comparing I/R to BNP groups, GFR did not differ significantly at any time point. There was no significant difference in uNGAL levels at 1 h (552 ± 358 versus 516 ± 259 ng/mL, P = 0.87) or 2 h (1073 ± 589 versus 989 ± 218 ng/mL, P = 0.79) between I/R and BNP. CONCLUSIONS: BNP does not reduce the renal injury biomarker, urinary NGAL, or preserve GFR in acute renal ischemia-reperfusion injury.

Growth phase-specific changes in the composition of E. coli transcription complexes.

In E. coli, a single oligomeric enzyme transcribes the genomic DNA, while multiple auxiliary proteins and regulatory RNA interact with the core RNA polymerase (RP) during different stages of the transcription cycle to influence its function. In this work, using fast protein isolation techniques combined with mass spectrometry (MS) and immuno-analyses, we studied growth phase-specific changes in the composition of E. coli transcription complexes. We show that RP isolated from actively growing cells is represented by prevalent double copy assemblies and single copy RP-RNA and RP-RNA-RapA complexes. We demonstrate that RpoD/σ70 obtained in fast purification protocols carries tightly associated RNA and show evidence pointing to a role of sigma-associated RNA in the formation of native RP-(RNA)-RpoD/σ70 (holoenzyme) complexes. We report that enzymes linked functionally to the metabolism of lipopolysaccharides co-purify with RP-RNA complexes and describe two classes of RP-associated molecules (phospholipids and putative phospholipid-rNT species). We hypothesize that these modifications could enable anchoring of RP-RNA and RNA in cell membranes. We also report that proteins loosely associated with ribosomes and degradosomes (S1, Hfq) co-purify with RP-RNA complexes isolated from actively growing cells - a result consistent with their proposed roles as adaptor-proteins. In contrast, GroEL, SecB, and SecA co-purified with RP obtained from cells harvested in early stationary phase. Our results demonstrate that fast, affinity chromatography-based isolation of large multi-protein assemblies in combination with MS can be used as a tool for analysis of their composition and the profiling of small protein-associated molecules (SPAM).

Validating the portal population of the United Kingdom Multiple Sclerosis Register.

The UK Multiple Sclerosis Register (UKMSR) is a large cohort study designed to capture 'real world' information about living with multiple sclerosis (MS) in the UK from diverse sources. The primary source of data is directly from people with Multiple Sclerosis (pwMS) captured by longitudinal questionnaires via an internet portal. This population's diagnosis of MS is self-reported and therefore unverified. The second data source is clinical data which is captured from MS Specialist Treatment centres across the UK. This includes a clinically confirmed diagnosis of MS (by Macdonald criteria) for consented patients. A proportion of the internet population have also been consented at their hospital making comparisons possible. This dataset is called the 'linked dataset'. The purpose of this paper is to examine the characteristics of the three datasets: the self-reported portal data, clinical data and linked data, in order to assess the validity of the self-reported portal data. The internet (n = 11,021) and clinical (n = 3,003) populations were studied for key shared characteristics. We found them to be closely matched for mean age at diagnosis (clinical = 37.39, portal = 39.28) and gender ratio (female %, portal = 73.1, clinical = 75.2). The Two Sample Kolmogorov-Smirnov test was for the continuous variables to examine is they were drawn from the same distribution. The null hypothesis was rejected only for age at diagnosis (D = 0.078, p < 0.01). The populations therefore, were drawn from different distributions, as there are more patients with relapsing disease in the clinical cohort. In all other analyses performed, the populations were shown to be drawn from the same distribution. Our analysis has shown that the UKMSR portal population is highly analogous to the entirely clinical (validated) population. This supports the validity of the self-reported diagnosis and therefore that the portal population can be utilised as a viable and valid cohort of people with Multiple Sclerosis for study.

Ranitidine does not affect chlormethiazole or indocyanine green disposition.

Cimetidine has been shown to inhibit hepatic mixed-function oxidase activity and to lower hepatic blood flow. It is not known whether these effects are related to its H2-receptor antagonism or to its intrinsic structure. Ranitidine is a more potent H2-receptor antagonist and differs structurally from cimetidine. In our study, ranitidine, 150 mg twice daily, had no effect on oral or systemic clearance of chlormethiazole, a sedative with a high clearance, and no effect on indocyanine green elimination.

Decreased oral warfarin clearance after ranitidine and cimetidine.

Oxidative metabolism inhibition of a number of drugs by cimetidine has been attributed to its imidazole ring, a hypothesis that has been supported by reports that ranitidine does not affect drug metabolism despite being five times as potent as cimetidine as an H2-receptor antagonist. In five healthy subjects ranitidine at 150 mg twice daily induced a 27% fall in apparent oral warfarin clearance. In the same subjects cimetidine at 1 gm/day induced a 36% decrease in warfarin clearance. In two of the subjects the experiment was repeated after giving 750 mg ranitidine per day and in two other subjects after 200 mg cimetidine twice daily. In both instances there was a stepwise fall in warfarin clearance with increasing doses. The data indicate that interference with drug metabolism by H2-receptor antagonists is not confined to cimetidine but that on a molar basis ranitidine and cimetidine are roughly equivalent in inhibiting warfarin clearance and that the effects are related to dose.

Management of penetrating lung injuries in civilian practice.

Recent reports of military thoracic injuries have advocated early thoracotomy and aggressive management of pulmonary injuries with resection as opposed to the more conservative and traditional treatment with chest tube thoracostomy. A retrospective study was therefore performed to determine the incidence of thoracotomy and lung resection in civilian injuries and to evaluate the effectiveness of treatment of these injuries. Between 1973 and 1985, in a series of 1,168 patients, there were 384 gunshot wounds and 784 stab wounds to the thorax. Two hundred eighty-three patients with a gunshot wound (74%) and 602 with a stab wound (77%) were treated with chest tubes alone. Sixty-eight patients (6% of the total) required operative repair of pulmonary hilar or parenchymal injury. Pulmonary resection was necessary in only 18 patients (nine with a gunshot wound and nine with a stab wound), and 10 patients had repair of hilar injuries (nine with a gunshot wound and one with a stab wound). Of patients requiring pulmonary resection, nine required wedge or segmental resection, six required lobectomy, and three patients required pneumonectomy. Mortality for all thoracic injuries was 2.3%: for those treated with chest tube alone, 0.7%; for pulmonary hilar injuries, 30%; for pulmonary parenchymal injuries, 8.6%; and for injuries necessitating lung resection, 28%. Most civilian lung injuries can be treated by tube thoracostomy alone. Although relatively few patients with primary pulmonary injury require thoracotomy, those that do are at significant risk and may require lung resection to control bleeding or hemoptysis or to remove destroyed or devitalized lung tissue.

The effect of renin-angiotensin system blockade on visceral blood flow during and after thoracic aortic cross-clamping.

Surgical procedures necessitating clamping of the thoracic aorta are associated with a high incidence of postoperative renal dysfunction. Plasma renin activity is elevated during and after thoracic aortic occlusion in animals. The pathophysiology of the renal dysfunction may involve the renin-angiotensin system. Blockade of the renin-angiotensin system was studied in a canine model during occlusion of the thoracic aorta. Saralasin, a competitive blocker of angiotensin II, and the converting enzyme inhibitor MK422 were studied. Sixteen animals were separated into three treatment groups: control (five animals), saralasin (five), and MK422 (six). All dogs underwent clamping of the thoracic aorta for 60 minutes. In control animals, plasma renin activity increased from 0.16 +/- 0.04 to 6.41 +/- 1.57 ng/ml/hr at 30 minutes after thoracic aortic occlusion (p less than 0.05). Thirty minutes after cross-clamp release, plasma renin activity remained 10 times greater than baseline, 1.47 +/- 0.20 ng/ml/hr (p less than 0.05). Renal blood flow was measured with 15 micron microspheres before, during, and after thoracic clamping. In control animals, renal cortical blood flow decreased during cross-clamping and remained below baseline after clamp release: baseline, 7.05 +/- 0.98 ml/gm/min (standard error of the mean); 30 min after clamp release, 3.77 +/- 0.43 ml/gm/min (standard error of the mean) (p less than 0.05). In the MK422 group, renal cortical blood flows returned to baseline after cross-clamp release: baseline, 6.38 +/- 0.49 ml/gm/min; 30 minutes after clamp release, 7.30 +/- 1.6 ml/gm/min. Infusion of MK422 after placement of the thoracic aortic cross-clamp resulted in normal renal blood flow after clamp release. This protective effect was not seen with saralasin. The resumption of normal renal cortical blood flow after the administration of the converting enzyme inhibitor MK422 suggests that elevated plasma renin activity may contribute to renal dysfunction after thoracic aortic occlusion.

A reappraisal of limited-stage undifferentiated carcinoma of the lung. Does stage I small cell undifferentiated carcinoma exist?

Patients with small cell undifferentiated carcinoma of the lung (SCUC) have a poor prognosis. Surgical excision is avoided if the diagnosis can be made with small biopsy specimens or cytologic preparations. We reviewed 323 consecutive patients with pulmonary neoplasms diagnosed as SCUC, oat cel carcinoma, and undifferentiated or poorly differentiated carcinoma. At the time of diagnosis, only 18 patients had neoplasms classified as clinical Stage I, and only one of these had SCUC after histologic review. Fifteen patients had atypical carcinoid, a tumor with features intermediate between ordinary bronchial carcinoid and SCUC. In two instances, there was insufficient tissue for definitive diagnosis. Cumulative survival of the 15 patients with Stage I atypical carcinoid tumor was 80% at 1 year and 60% at most recent follow-up (mean follow-up 20 months). Mean survival for the 305 remaining patients was 7.9 months. Atypical carcinoid may be misdiagnosed as SCUC or poorly differentiated carcinoma, particularly with limited tissue samples or cytologic preparations. Stage I SCUC exists but is exceedingly rare. Many examples of purported Stage I SCUC probably represent atypical carcinoid. Because atypical carcinoid has a far better prognosis than SCUC, precise diagnosis is important and surgical resection should be considered.

Standard biplane roentgenography is highly sensitive in documenting mediastinal masses.

The records of 30 patients with mediastinal masses were reviewed to evaluate the signs, symptoms, and preoperative tests that were most useful in diagnosing and localizing the masses. Sixteen (53%) of the tumors were benign, and 14 (47%) were malignant. Twenty patients were seen with symptoms. The most common symptoms suggesting malignancy were pain, weight loss, fever, and cough. Four of the 5 patients who were truly asymptomatic had benign lesions. All 4 patients with palpable adenopathy had malignant tumors. Posteroanterior and lateral chest roentgenograms detected the mediastinal mass in 29 (97%) of the 30 patients. All patients were operated on for tissue diagnosis or resection (13, median sternotomy; 8, right thoracotomy; 3, left thoracotomy; 2, low anterior cervical approach). Eight patients underwent mediastinoscopy, which was diagnostic in 6 and obviated the need for operation in 4. It was of particular value for patients with lymphoma, who can be managed without resection.

Anterolateral thoracotomy as an alternative to repeat median sternotomy for replacement of the mitral valve.

Median sternotomy is the most common approach for repeat cardiac surgery despite the potential complications of cardiac injury. Right anterolateral thoracotomy has been recommended as an alternative for patients undergoing mitral valve replacement, but data supporting one approach over the other do not exist. To compare these procedures, the records of 43 patients who had had a previous median sternotomy and who underwent mitral valve replacement were reviewed. No statistically significant differences between patients undergoing repeat median sternotomy (33 patients) and those undergoing right anterolateral thoracotomy (10 patients) were demonstrable when compared for age, gender, New York Heart Association Functional Class, other diseased valves, urgency of operation, indication for operation, type of valve removed, type of valve implanted, length of postoperative hospitalization, length of operation, days of ventilatory support, length of intensive care unit stay, and survival (90% for thoracotomy group; 76% for median sternotomy group; p, NS). Significant differences between the two groups, favoring right anterolateral thoracotomy, were apparent when comparisons were made for length of perfusion (means, 94.8 min, thoracotomy group; 121.4 min, sternotomy group; p = .03), incidence of reexploration (0%, thoracotomy group; 13%, sternotomy group; p = .001), and blood transfusion (means, 5.3 units, thoracotomy group; 11.4 units, sternotomy group; p = .003). Right anterolateral thoracotomy is an effective alternative to repeat median sternotomy for replacement of the mitral valve in patients who have had a previous median sternotomy.

Unanticipated postoperative ventricular tachyarrhythmias.

Eighteen (1.4%) of 1,251 patients who underwent cardiac operations during a three-year period had new sustained ventricular tachycardia (12 patients) or ventricular fibrillation (6 patients) not caused by but resulting in hemodynamic compromise. In 13 patients, the initial arrhythmia occurred in the first 48 hours postoperatively. Lidocaine was being administered to 10 of these patients for suppression of previously noted ventricular ectopy, but it did not prevent the occurrence of the arrhythmia. The initial episode was fatal for 5 patients. Two of these deaths were directly related to the adverse effects of the antiarrhythmic agents used to suppress ventricular tachycardia or fibrillation. Five of 10 survivors underwent electrophysiological studies after initial resuscitation. In all 5, programmed ventricular stimulation reproduced the clinical arrhythmia. There have been 2 late sudden deaths in patients who either did not undergo or remained uncontrolled at electrophysiological study during serial drug trials. Our experience suggests that a cardiac operation may unmask or induce potentially lethal arrhythmias that previously had not been apparent. Pharmacological suppression of ventricular ectopy does not necessarily prevent ventricular tachycardia or ventricular fibrillation in the early postoperative period. Electrophysiological study may be helpful in determining the appropriate prophylactic therapy in such patients.

Operative closure of patent ductus arteriosus in premature infants in the neonatal intensive care unit.

Fifty-two premature infants underwent hemoclip closure of patent ductus arteriosus in the neonatal intensive care unit after a brief trial of fluid restriction and diuretics. Indomethacin was used in only four patients. The median time from diagnosis to operation was 3 days. There were no deaths directly attributable to operation. Nine operative complications developed in nine patients (17 percent). There were no surgical infections. Complications related to prematurity resulted in 20 deaths (38 percent). Patent ductus arteriosus closure in the neonatal intensive care unit prevented the complications of hypothermia, inadvertent extubation, and interruption of vascular access and monitoring. Early operative closure in the neonatal intensive care unit is the treatment of choice in most premature infants with patent ductus arteriosus.

Primary small bowel malignancies.

Fifty-five patients with primary small bowel malignancies were evaluated from 1955 to 1983. Twenty-seven patients (49%) had carcinoid tumors, 16 (29%) had adenocarcinomas, and 12 (22%) had leiomyosarcomas. The average age at presentation was 68 years (range: carcinoids, 27-82; leiomyosarcomas, 36-75; adenocarcinomas, 40-83). Carcinoids and leiomyosarcomas were 1.7 and 2.0 times, respectively, more common in men; adenocarcinomas showed no sex predominance. Eighty-nine per cent of all patients had symptoms: abdominal pain in 65 per cent, obstruction in 23 per cent, bleeding in 8 per cent, and palpable mass in 5 per cent. Although 27 per cent of carcinoid patients were asymptomatic, 40 per cent exhibited the carcinoid syndrome. Symptoms were longstanding in the majority of cases, and, at the time of diagnosis, 49 per cent of the carcinomas were metastatic. Fifty-five per cent of the tumors were in the ileum, 24 per cent in the jejunum, and 21 per cent in the duodenum. Fifty-five patients (89%) underwent resection for palliation or cure. Five adenocarcinoma patients (32%) survived 1 year, and one (6%) lived 10 years. Twenty-five per cent of leiomyosarcoma patients survived for 10 years. Eighty-seven per cent of patients with carcinoids survived for 1 year, 39 per cent for 5 years, and 22 per cent for 10 years. Previous reports have documented the difficulty of diagnosing these lesions, as does the present study. A higher degree of physician awareness and a more aggressive investigation of referable symptoms should lead to earlier treatment and better long-term results.

The adult ductus. Surgical results and long-term follow-up.

Surgical treatment for the adult patent ductus can be a safe procedure if adequate aortic control is obtained. Long-term results are satisfactory, except for patients with pulmonary hypertension, of whom only 50 per cent obtain a good result. We believe operative treatment is indicated in the asymptomatic adult patient with patent ductus arteriosus, because one cannot predict which patients will develop pulmonary hypertension. In our group pulmonary hypertension developed in patients whose average age was the same as those who were asymptomatic. Those patients who are New York Heart Association (NYHA) class III usually have pulmonary hypertension, large ductus, and calcification, all of which could cause operative complications. Therefore, it is relatively easy to predict by symptoms alone which patients have the highest operative risk.

The effect of an antacid and food on the absorption of cimetidine and ranitidine.

The effect of varying doses of a liquid antacid preparation containing magnesium hydroxide, aluminum hydroxide and simethicone on the absorption of the H2-receptor antagonists, cimetidine and ranitidine, was determined in 2 groups of 11 volunteers; one group fasted and one group fed a standardized breakfast. The antacid alone caused a significant decrease in the AUC of cimetidine (24%). Similarly, concomitant antacid caused a 59% decrease in the AUC of ranitidine. There were no effects on any of the other pharmacokinetic parameters examined. The absorption of both drugs was similar in fasted and fed volunteers, but in the fed volunteers the antacid did not produce the decrease in AUC seen in the fasted volunteers. These data suggest that H2-receptor antagonists should not be taken at the same time as antacids.

Studies on the mechanisms of action of activated charcoal on theophylline pharmacokinetics.

Oral administration of repeated doses of activated charcoal to volunteers and dogs significantly increased the systemic clearance of intravenously administered theophylline and decreased its elimination half-life. This effect is most likely to be due to theophylline entering the gut and being adsorbed onto the charcoal. The mechanism by which intravenously administered theophylline enters the gut has been examined. Its biliary excretion after intravenous administration to patients with T-tube biliary drainage accounted for 0.28% of the dose and a similarly small biliary excretion was found in dogs. In the latter total biliary diversion had no effect on the clearance or half-life of theophylline after intravenous administration. In two dogs the theophylline content of jejunal aspirate was comparable with that of simultaneously withdrawn venous plasma samples. These results suggest that the presence of charcoal in the gut represents a sink adsorbing theophylline entering the lumen by diffusion across the intestinal wall, and by this mechanism it increases clearance of the drug even after intravenous administration.

Hepatobiliary scan with delayed gallbladder visualization in a case of acute appendicitis.

A 40-year-old woman presented with acute epigastric pain with vomiting. Within 24 hours, the pain spread to the right periumbilical region. Tc-99m disofenin hepatobiliary scan failed to demonstrate the gallbladder on a 60-minute view. The presumative diagnosis of acute cholecystitis was thought to be confirmed on this basis by the patient's physicians. However, a 75-minute view demonstrated filling of the gallbladder. In hepatobiliary scanning for acute abdominal pain, delayed views (2 to 24 hours) are recommended when the gallbladder is not visualized on the 60-minute view. If the gallbladder is visualized, cystic duct obstruction can be excluded and diagnoses such as pancreatitis, acalculous cholecystitis, and acute appendicitis should be investigated.